This invention relates to a process for producing the optically pure C.sub.10 -C.sub.24 fragment of FK-506 useful as an intermediate in synthesizing the FK-506 immunosuppressant and derivatives thereof.
The novel 23-membered tricyclomacrolide FK-506 recently isolated and characterized by Tanaka, Kuroda and co-workers (J. Am. Chem. Soc. 109, 5031 (1987) and EPO Publication No. 0184162) has been shown to possess exceptional immunosuppressive activity. The potential usefulness of such an agent in bone narrow and organ transplantations coupled with its unique structural features has prompted many in the field to initiate an effort towards the total synthesis of FK-506.
A highly stereoselective general synthesis of a protected C.sub.10 -C.sub.18 subunit, in its correct absolute configuration, has been achieved as reported by D. Askin, R. P. Volante, R. A. Reamer, K. M. Ryan and I. Shinkai in Tetrahedron Letters 29, 277, 281 and 4245 (1988), hereby incoporated by reference. See also: (a) Villalobos, A; Danishefsky, S. J., J. Org. Chem., 54, 12(1989); (b) Schreiber, S. L.; Smith, D. B., Ibid, 54 9(1989); (c) Egbertson, M.; Damishefsky, S. J., Ibid, 54, 11(1989); (d) Scheiber, S. L.; Sammakia, T.; Uehling, D. E., Ibid, 54, 16(1989).
A highly selective general synthesis of a protected C.sub.10 -C.sub.23 subunit of FK-506, in its correct absolute configuration has been achieved as reported by A. B. Smith III and K. J. Hale (Tetrahedron Letters 30, 1037(1989)). That process has the disadvantages of poor stereoselectivity at the C.sub.11 center (fractional crystallization is required to separate the stereoisomers) and substituents at the C.sub.10 and C.sub.21 centers which do not correspond to the natural product. Furthermore, those substituents can not be readily converted to the substituents of the natural product.
What is needed is an overall general synthesis utilizing readily available starting materials which would allow the synthesis of the C.sub.10 -C.sub.24 fragment of FK-506 incorporating the naturally occurring substituents and also allow for other substituents to be incorporated. Such fragments may be utilized in a convergent total synthesis of FK-506 and related macrolides, the latter which may exhibit greater immunosuppressant acitivity then the naturally occurring form itself.